Based upon the analysis of 214 families submitted to the Breast Cancer Linkage Consortium and on more recent data collected in our laboratories and from our collaborators, it has become Clear that a substantial proportion, perhaps even the majority, of familial breast cancer is not due to the BRCA1 locus on chromosome 17q. The objective of this collaborative proposal between the University of Utah and the Institute of Cancer Research in England is to identify one or more additional genes which are responsible for the breast cancer cases in these unlinked families. From an existing pool of families collected as part of our ongoing studies of breast and ovarian cancer, we have identified a set of 22 extended families for which linkage to 17q has been reliably excluded through genotyping of a set of highly polymorphic markers in the BRCA1 region. These families have been stratified by the presence of ovarian cancer and/or male breast cancer in order to minimize potential further genetic heterogeneity. To date, we have gathered nearly 400 blood samples from members of these kindreds. We will use genetic linkage analysis to test a set of hypothesized candidate genes or candidate regions for breast/ovarian cancer in these families. These analyses will concentrate on genes/regions which have been implicated in familial breast cancer based upon multiple lines of evidence: biological plausibility, loss of heterozygosity in tumors, and genes implicated from previous linkage studies. If, as is likely, the set of candidate loci do not account for the inherited susceptibility in all (or perhaps, any) families, the remaining unlinked families will be used in a genomic search. We will use a potential set of over 400 highly polymorphic markers spread throughout the genome to identify gene(s) responsible for the inherited susceptibility. In this proposal we demonstrate through simulation studies that these 22 families provide high power for finding such genes, even if additional genetic heterogeneity exists. Once linkage has been established to a specific chromosomal region, we will test a series of other known marker loci in the region in order to identify the closest flanking markers for each breast cancer susceptibility gene identified.